Among the more than 90 identified genetic risk loci for late-onset Alzheimer's disease (AD) and related dementias, the apolipoprotein E (APOE) gene ɛ2/ɛ3/ɛ4 polymorphisms remain the longstanding benchmark for genetic disease risk with a consistently large effect across studies1-10. Despite this massive signal, the exact mechanisms by which ɛ4 increases and ɛ2 decreases dementia risk remain poorly understood. Notably, recent trials of anti-amyloid therapies suggest less efficacy and higher risks of severe side effects in ε4 carriers11-13, hampering the treatment of those with the highest unmet need. To improve our understanding of the genetic architecture of AD in the context of its main genetic driver, we performed genome-wide association studies (GWASs) stratified by ε4 and ε2 carrier status. HP1BP3, SLC50A1, PTPRC, NPAS3, DDHD1, CHST9, SMYD2, PRAMEF1 and GFRA1 emerged as new genomic signals for AD risk, appearing only when stratified by APOE carrier status. DDHD1 appeared especially promising, showing protective effects in ε4 carriers, being identified as an expression quantitative trait locus and being involved in rare neuronal diseases. Such APOE-stratified insights may help understand and overcome side effects, inform clinical trial enrollment strategies, and create the scientific basis for targeted, mechanism-driven therapies in neurodegenerative diseases.
J. Thomassen, H. Leonard, Brittany Ulms et al.· Nature Genetics· 0 citations
Abstract Background Electroconvulsive therapy (ECT) is among the most effective treatments for severe and treatment-resistant depression. Despite more than 90 years of clinical use, its underlying neurobiological mechanisms remain incompletely understood. One prominent hypothesis suggests that ECT induces neuroplastic changes, supported by evidence of volumetric brain alterations in regions implicated in depression and increases in peripheral neurotrophins [1,2]. In contrast, critical perspectives interpret post-ECT volumetric changes as transient oedema or raise concerns about potential neuronal damage. Aims & Objectives The present prospective study aimed to investigate ECT-associated changes in brain structure and functional connectivity using magnetic resonance imaging (MRI), alongside cerebrospinal fluid (CSF) markers of neuronal and glial injury, in patients with severe depression. Method Thirteen hospitalized patients with treatment-resistant depression (mean age 41 ± 9.6 years; baseline Hamilton Depression Rating Scale (HAMD17) score 26 ± 3.1, indicating severe depression) underwent a course of eight bilateral ECT sessions. ECT was administered using a Thymatron IV device under general anesthesia with either methohexital or ketofol and succinylcholine as muscle relaxant; stimulus dosing was determined via individual seizure threshold titration. All patients remained on stable antidepressant medication throughout the treatment period. Structural and resting-state MRI scans were acquired before the first and after the eighth ECT session using a Siemens MAGNETOM Prisma 3T scanner, accompanied by lumbar puncture at both time points. Gray matter volume changes were assessed using a repeated-measures analysis of covariance (rmANCOVA) with age and sex as covariates. Brain segmentation was performed with FreeSurfer 7.1, and statistical analyses were conducted using SPSS Version 25. Resting-state functional connectivity analyses focused on the default mode network (DMN) as a seed region, with preprocessing performed in SPM12. CSF concentrations of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) were quantified using single molecule array (SIMOA) technology, with statistical analyses conducted in RStudio. Given the exploratory nature of the study, results are reported without correction for multiple comparisons. Results Following ECT, depressive symptoms significantly improved, as reflected by a marked reduction in HAMD17 scores (t = 6.1, p < 0.001). Structural MRI revealed a significant, uncorrected increase in gray matter volume confined to the left precuneus (F = 6.016, p = 0.044). Functional connectivity analyses demonstrated reduced connectivity between the DMN and the cerebellum (t = 6.61, p < 0.001) as well as the middle occipital gyrus (t = 5.85, p = 0.002) following ECT. Importantly, no significant changes in CSF levels of NfL (p = 0.213) or GFAP (p = 0.362) were observed. Discussion & Conclusions Consistent with previous neuroimaging findings, ECT was associated with alterations in brain structure and DMN connectivity – a network critically involved in the pathophysiology of depression [3]. Notably, the absence of changes in CSF markers of neuronal or glial injury provides no evidence for ECT-related neuronal damage in this cohort. Whether the observed neuroimaging changes represent a necessary component of ECT’s antidepressant efficacy remains an open question. The small sample size and exploratory design constitute important limitations and warrant replication in larger, controlled studies.
P. Baldinger-Melich, S. Riessland, B. Spurny-Dworak et al.· International Journal of Neu...· 0 citations
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